Smoking elicit drugs such as marijuana causes immunosuppression and increases the risk of contracting infections particularly in HIV-seropositive individuals. Delta9-tetrahydrocannabinol (THC), the major psychoactive principle marijuana has been identified as a critical immunosuppressive agent, although the mechanism by which it induces toxicity is not clear. Moreover, recreational use of marijuana during pregnancy remains a major health problem and very little is known about the consequences of prenatal exposure to THC on the immune system. Interest in cannabinoid research has increased tremendously in recent years since the discovery of cannabinoid receptors and the endogenous ligands for these receptors. The fact that cannabinoid CB2 receptors are almost exclusively expressed on immune cells raises exciting questions on the role and significance of such receptors and their endogenous ligands in immunoregulation. Recent studies from our laboratory demonstrated that cannabinoids induce apoptosis in lymphoid organs and suppress lymphocyte functions. In the current study, we will investigate the role of apoptosis in cannabinoid-induced immunomodulation following prenatal and postnatal exposure. In aim1, we will test the hypothesis that THC triggers apoptosis and immunornodulation by binding to CB1 and/or CB2 receptors on immune cells using mice deficient in CB1, CB2, or both CB1/CB2 receptors. In aim 2, we will test the hypothesis that THC-induced apoptosis is responsible for decreased T cell response to bacterial antigens by using the superantigen model and analyzing antigen-specific Vbeta3+ and Vbetal 1+ T cells. In aim 3, the mechanism by which THC induces apoptosis in T cells via the death receptor pathway and/or the mitochondrial pathway will be studied using cDNA array and mutant cell lines that are deficient in FADD, caspases and members of bcl-2 gene family. In aim 4, we will test whether prenatal exposure to THC alters positive and negative selection of T cells in the thymus and thereby affects the T cell repertoire postnatally. Lastly, in aim 5, the hypothesis that endogenous cannabinoids such as an and amide regulate the immune functions by triggering apoptosis using FAAH knockout mice will be tested. In summary, the aims listed above form the basis for understanding the mechanism of induction of apoptosis in immune cells by exogenous and endogenous cannabinoids. These studies are particularly important in understanding how substance abuse by individuals who are at a higher risk for contracting HIV infection, HIV-infected individuals, and HIV-infected pregnant mothers, will influence the course of infection.